Description (adapted from applicants abstract) The human neonate and young infant are unduly susceptible to infection with intracellular pathogens, including Mycobacterium tuberculosis (Mtb) and herpes simplex virus (HSV). Control of infection with intracellular pathogens depends on the development of an effective T cell-dependent, cellular immune response. For this response to protect the host, it must develop before the microbe produces long term injury or death and be both sufficiently robust and of the appropriate quality to eradicate or control active infection. For most intracellular pathogens, the generation of Th1 (i.e., T cells that produce IFN-g ) and/or cytolytic T cells (CTL) and activation of macrophages are essential components of a protective immune response. T cells from newborns and young infants have the potential to develop Th1 T cells and CTL, but the efficiency/rate with which this occurs is reduced. Aims 1-3 will evaluate the contribution of co-stimulatory molecules (i.e., CD28- CD80/86 and CD40 ligand-CD40) and pro-inflammatory cytokines expressed by antigen-presenting cells (e.g., dendritic cells and macrophages) and other cells of the innate immune in the development of a protective, antigen-specific T cell response to these infections. Aim 4 will explore the role which DNA methylation plays in the regulation of T cell functions relevant to the development of a protective T cell response. Collectively, these aims address the basis for the greater susceptibility of the neonate and young infant to these infections. Aim 1: Determine the contribution of costimulatory interactions between T cells and antigen-presenting cells (APC) and of TNF acting locally in the lung in the development of antigen-specific T cells and the control of primary pulmonary infection due to Mtb. Aim 2: Determine the contribution of costimulatory interactions and effects of HSV mediated inhibition of antigen presentation by class I major histocompatibility complex molecules (MHC class I) in the development of a protective T cell response. Aim 3: Determine whether dendritic antigen-presenting cells (DC) from human neonates differ from those from adults in their expression of MHC and costimulatory molecules and production of cytokines favoring the development of Th1 T cells and CTL in response to challenge with Mtb or HSV in vitro. Aim 4. Determine the role of DNA methylation in the regulation of IFN-g production and greater dependence on costimulation of naive, neonatal T cells.